The study investigators collected and analyzed individual-level genetic data from 392,220 participants drawn from 3 cohort studies conducted in Europe between January 1991 and July 2018. The data were assessed for 6 genetic variations of lipoprotein lipase inhibitors reported to be independently associated with lowering triglycerides (including loss-of-function variants in ANGPTL4 and ANGPTL3) and 58 genetic variations from different independent genomic regions associated with LDL-C levels (including the genetic variants HMGCR, NPC1L1, and PCSK9).

The investigators used weighted generalized linear regression models to test associations of these genetic variants with cardiometabolic outcomes.

The study results show that triglyceride-lowering alleles in lipoprotein lipase were associated with protection from coronary artery disease and type 2 diabetes in combined and individual variant analyses. In the independent analyses, the ANGPTL4 p.Glu40Lys variant was associated with lower risk of coronary disease and diabetes.

Loss-of-function variants in ANGPTL3 reduced the risk of coronary disease by approximately 34% (odds ratio [OR], 0.66; 95% CI, 0.52-0.83; P <.001; P =.99 for heterogeneity) in carriers vs noncarriers; they also had a stronger association with lowering coronary disease risk over the LDL-C–lowering alleles.

For the LDL-C–lowering variants, including HMGCR, NPC1L1, and PCSK9 variants, a difference of 0.23 standard deviations in genetic score was consistently associated with lowering odds of coronary disease by approximately 10% (OR, 0.90; 95% CI, 0.89-0.91; P =.86 for heterogeneity).

Limitations of the study included using triglyceride levels as a proxy for measuring genetic differences in lipoprotein lipase-mediated lipolysis. Consequences of short-term pharmacological modulation of this pathway used in clinical trials and practice may differ from genetically determined differences over several decades.

Triglyceride-lowering alleles in the lipoprotein lipase pathway and LDL-C–lowering genetic mechanisms are independently associated with improving cardiometabolic outcomes and are indicated to lower risk of coronary artery disease and type 2 diabetes.

These findings provide evidence to support the development of enhanced lipoprotein lipase-mediated lipolysis to treat individuals at risk for coronary disease and type 2 diabetes and to further reduce risk of cardiovascular disease in individuals taking LDL-C–lowering therapy.

The American College of Cardiology published an expert consensus statement regarding decision considerations for novel cardiovascular risk reduction therapies in patients with type 2 diabetes and atherosclerotic cardiovascular disease.